Synthesis and bioactivities of diamide derivatives containing a phenazine-1-carboxamide scaffold

Article abstract of DOI:10.1080/14786419.2018.1451997

Taking natural product phenazine-1-carboxamide (PCN) as a lead compound, a series of novel phenazine-1-carboxylic acid diamide derivatives were designed and synthesised. Their structures were confirmed by ¹H-NMR and HRMS. The bioassays showed that some of the target compounds exhibited promising in vitro fungicidal activities, and exhibited excellent and selective herbicidal activities. Particularly, compounds c, h, o and s displayed root length inhibition activities against barnyard grass with the rate of more than 80%. Compound c exhibited the best activity among all the target compounds against barnyard grass stalk length with the IC₅₀ value of 0.158?mmol/L, and compound o exhibited the best and wide spectrum inhibition against barnyard grass root length and rape in both root length and stalk length herbicidal activities with its IC₅₀ values of 0.067, 0.048 and 0.059?mmol/L respectively. The analysis of preliminary Structure-Activity Relationships provides the theoretical basis for further design of phenazine-1-carboxylic acid.

Full text of DOI:10.1080/14786419.2018.1451997

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: http://www.tandfonline.com/loi/gnpl20
Synthesis and bioactivities of diamide derivatives
containing a phenazine-1-carboxamide scaffold
Xiang Zhu, Min Zhang, Linhua Yu, Zhihong Xu, Dan Yang, Xiaoying Du,
Qinglai Wu & Junkai Li
To cite this article: Xiang Zhu, Min Zhang, Linhua Yu, Zhihong Xu, Dan Yang, Xiaoying
Du, Qinglai Wu & Junkai Li (2018): Synthesis and bioactivities of diamide derivatives
containing a phenazine-1-carboxamide scaffold, Natural Product Research, DOI:
10.1080/14786419.2018.1451997
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Natural Product research, 2018
ꢁꢁpꢂ://ꢃꢄi.ꢄꢅg/10.1080/14786419.2018.1451997
ꢀ
Synthesis and bioactivities of diamide derivatives containing
a phenazine-1-carboxamide scaffold
a
a
a
a
a
a
Xiang Zhu , Min Zhang , Linhua Yu , Zhihong Xu , Dan Yang , Xiaoying Du ,
a,b
a,c
Qinglai Wu and Junkai Li
ꢆ
b
sꢇꢀꢄꢄꢈ ꢄf agꢅiꢇꢉꢈꢁꢉꢅꢊ, Yꢆngꢁzꢊ univꢊꢅꢂiꢁy, Jingzꢀꢄꢉ, cꢀinꢆ; enginꢊꢊꢅing rꢊꢂꢊꢆꢅꢇꢀ cꢊnꢁꢊꢅ ꢄf eꢇꢄꢈꢄgy ꢆnꢃ
ꢇ
agꢅiꢇꢉꢈꢁꢉꢅꢆꢈ uꢂꢊ ꢄf Wꢊꢁꢈꢆnꢃ, Miniꢂꢁꢅy ꢄf eꢃꢉꢇꢆꢁiꢄn, Yꢆngꢁzꢊ univꢊꢅꢂiꢁy, Jingzꢀꢄꢉ, cꢀinꢆ; hꢉbꢊi cꢄꢈꢈꢆbꢄꢅꢆꢁivꢊ
Innꢄvꢆꢁiꢄn cꢊnꢁꢅꢊ fꢄꢅ Gꢅꢆin Inꢃꢉꢂꢁꢅy, Yꢆngꢁzꢊ univꢊꢅꢂiꢁy, Jingzꢀꢄꢉ, cꢀinꢆ
ABSTRACT
ARTICLE HISTORY
Taking natural product phenazine-1-carboxamide (PCN) as a lead
compound, a series of novel phenazine-1-carboxylic acid diamide
derivatives were designed and synthesised. Their structures were
rꢊꢇꢊivꢊꢃ 28 oꢇꢁꢄbꢊꢅ 2017
aꢇꢇꢊpꢁꢊꢃ 10 Mꢆꢅꢇꢀ 2018
KEYWORDS
1
confirmed by H-NMR and HRMS. The bioassays showed that some of
Pꢀꢊnꢆzinꢊ-1-ꢇꢆꢅbꢄxyꢈiꢇ
ꢆꢇiꢃ; ꢂynꢁꢀꢊꢂiꢂ; ꢃiꢆmiꢃꢊ
ꢃꢊꢅivꢆꢁivꢊꢂ; fꢉngiꢇiꢃꢆꢈ
ꢆꢇꢁiviꢁy; ꢀꢊꢅbiꢇiꢃꢆꢈ ꢆꢇꢁiviꢁy
the target compounds exhibited promising in vitro fungicidal activities,
and exhibited excellent and selective herbicidal activities. Particularly,
compounds c, h, o and s displayed root length inhibition activities
against barnyard grass with the rate of more than 80%. Compound c
exhibited the best activity among all the target compounds against
barnyard grass stalk length with the IC50 value of 0.158 mmol/L,
and compound o exhibited the best and wide spectrum inhibition
against barnyard grass root length and rape in both root length and
stalk length herbicidal activities with its IC50 values of 0.067, 0.048
and 0.059 mmol/L respectively. The analysis of preliminary Structure-
Activity Relationships provides the theoretical basis for further design
of phenazine-1-carboxylic acid.
CONTACT Xiꢆꢄying dꢉ
Qingꢊꢅ539@163.ꢇꢄm; Qingꢈꢆi Wꢉ
wqꢈ106@163.ꢇꢄm; Jꢉnkꢆi li
jꢉnkꢆiꢈi@ꢂinꢆ.ꢇꢄm
sꢉppꢈꢊmꢊnꢁꢆꢈ ꢃꢆꢁꢆ fꢄꢅ ꢁꢀiꢂ ꢆꢅꢁiꢇꢈꢊ ꢇꢆn bꢊ ꢆꢇꢇꢊꢂꢂꢊꢃ ꢀꢁꢁpꢂ://ꢃꢄi.ꢄꢅg/10.1080/14786419.2018.1451997.
©
2018 Infꢄꢅmꢆ uK limiꢁꢊꢃ, ꢁꢅꢆꢃing ꢆꢂ tꢆyꢈꢄꢅ & Fꢅꢆnꢇiꢂ Gꢅꢄꢉp

2
X. ZHU ET AL.
1
. Introduction
Phenazine-1-carboxamide (PCN, Figure 1) is a very important natural analogue of Phenazine-
-carboxylic acid (PCA, Figure 1), often isolated from the metabolites of Pseudomonas and
Streptomycetes (Gao et al. 2012; Puopolo et al. 2013; Hu et al. 2005; Laursen and Nielsen
004), showed five to ten times in fungicidal activity against Rhizoctonia solani as much as
PCA which registered as a biofungicide‘Shenqinbactin’against sheath blight on rice in China
Commare et al. 2002; Su et al. 2010; Zhou et al. 2010). In 2010, a series of structurally diverse
1
2
(
phenazine-1-carboxylic acid amide and diamide derivatives were designed and synthesised
byYe Long et al., the biological evaluation against R. solani indicated that some compounds
exhibited a significant level of activity with IC values 8 to 23-fold lower than that of PCA
5
0
(
Ye et al. 2010). Noteworthy, compound A and B (Figure 1) as the diamide analogues also
exhibited excellent fungicidal activities against R. solani.
Diamides are significant organic compounds with various biological activities, such as
antibacterial (Wang et al. 2017), anti-tumor (Ubaradka et al. 2015; Zabiulla et al. 2016), anti-
fungal (Sharma et al. 2008; Nayyab et al. 2017; Pejchalová et al. 2017), insecticidal (Clark et
al. 2008; Zhang et al. 2012), antiviral and anti-inflammatory activities (Rajakumar et al. 2012;
Saudi et al. 2016), etc. For example, both penicillin (Figure 2(C)) which first isolated by British
bacteriologist Fleming (Gaynes 2017), and the synthesised compound amoxicillin (Figure
2(D)), both have played important roles in protecting human health (Van et al. 2016). In
recent years, diamides have been more and more important in agrochemicals, such as some
commercialised pesticides, chlorantraniliprole (Figure 2(E)) and flubendiamide (Figure 2(F)),
displaying high effective insecticidal activities at a lower concentration and safe for mam-
mals, and applied widely as effective insecticides for the control of lepidoptera pests
(
Kavallieratos et al. 2013; Cui et al. 2017). Because of the low toxicity and high efficiency, the
research of diamides has become a hot topic in new pesticide creation.
Combination of active substructure and natural lead compounds is a very important
method for novel pesticide creation (Prabhakar et al. 2003). In this study, to find higher
bioactive lead compounds, a series of PCA-diamide derivatives (a–s, Figure 3) were designed
and synthesised by using natural product phenazine-1-carboxamide (PCN) as a lead com-
pound. Considering the structural and chemical diversity and to discuss their possible
Figure 1. sꢁꢅꢉꢇꢁꢉꢅꢊꢂ ꢄf PcN, Pca ꢆnꢃ Pca ꢃiꢆmiꢃꢊ ꢆnꢆꢈꢄgꢉꢊꢂ.

NATURAL PRODUCT RESEARCH
3
Figure 2. sꢁꢅꢉꢇꢁꢉꢅꢊꢂ ꢄf ꢂꢄmꢊ ꢃiꢆmiꢃꢊꢂ.
Structure-Activity Relationships (SARs). Different active substructures, such as alkanoyl
groups and aroyl groups, were introduced into the target compounds a-s. All target com-
pounds were evaluated for their fungicidal and herbicidal activities.
2
. Results and discussion
2
.1. Chemistry
The synthetic route of all target compounds a-s is described in Figure 3. Treatment of PCA
with oxalyl chloride at reflux temperature in CH Cl solution afforded intermediate 2 after
2
2
the evaporation of CH Cl . And the methyl ester of PCA 3 was prepared by adding excessive
2
2
methyl alcohol into intermediate 2, ammonolysis reaction of PCA methyl ester with ethyl-
enediamine in the solution of CH OH afforded intermediate 4. Reacted corresponding acids
3
5
with SOCl at reflux temperature afforded intermediate 6 after the evaporation of SOCl .
2
2
The target compounds a-s were then synthesised by reacting compound 4 to corresponding
intermediate 6 in CH Cl , and utilising triethylamine as a base at 0 °C. The structures of
2
2
1
derivatives a-s were characterised by H-NMR, and high resolution mass spectrum (HR-MS).
Analysis data of all the synthesised compounds are available in Supplementary Information).
(
2
.2. Fungicidal activities
Firstly, the fungicidal activities of all target compounds a-s were screened by using the
mycelium growth rate method against six phytopathogenic fungi (Chen 1991), Rhizoctonia
solani, Fusaium graminearum, Altemaria solani, Fusarium oxysporum, Sclerotinia sclerotiorum
and Pyricularia oryzae, at a concentration of 0.2 mmol/L. The phenazine-1carboxylic acid
(
PCA) was used as the positive control. Their fungicidal activities are showed in Table 1.
Results indicated that all target compounds a-s showed some in vitro fungicidal activities
against six phytopathogenic fungi, but most lower than PCA. Among the tested fungi,

4
X. ZHU ET AL.
Figure 3. synꢁꢀꢊꢁiꢇ ꢅꢄꢉꢁꢊ ꢄf ꢁꢀꢊ ꢁꢆꢅgꢊꢁ ꢇꢄmpꢄꢉnꢃꢂ a-s. (A) oxꢆꢈyꢈ ꢇꢀꢈꢄꢅiꢃꢊ, ch cꢈ , dMF, ꢅꢊflꢉx, 8 ꢀ; (B)
2
2
mꢊꢁꢀyꢈ ꢆꢈꢇꢄꢀꢄꢈ, ꢅꢄꢄm ꢁꢊmpꢊꢅꢆꢁꢉꢅꢊ, 1 ꢀ; (C) ꢊꢁꢀyꢈꢊnꢊꢃiꢆminꢊ, ch oh, ꢅꢄꢄm ꢁꢊmpꢊꢅꢆꢁꢉꢅꢊ, 0 °c ꢁꢄ ꢅꢊflꢉx,
3
2
ꢀ; (D) socꢈ , ꢅꢊflꢉx, 6 ꢀ; (E) inꢁꢊꢅmꢊꢃiꢆꢁꢊ 6, 0 °c, 1 ꢀ.
2
compounds a-s have the best fungicidal activities against R. solani and A. solani, with some
compounds showing the inhibitory rates of more than 50% (f, g, k, q). Particularly, compound
k showed the most potent fungicidal activities against R. solani and compound f showed
the best fungicidal activities against P. oryzae with the inhibitory rates of 72.7 and 82.0%
respectively. On the whole, through the discussion of Structure-Activity Relationships, we
can get a conclusion that the structures of R as aroyl groups are more active than as alkanoyl
groups. And the substituents of the aroyl groups in the para-position displayed higher fun-
gicidal activities than in other position.
2
.3. Herbicidal activities
The herbicidal activities of all target compounds a-s were tested by using a plate method
against barnyard grass (gramineae) and rape (dicotyledones) (Chen 1991), at a dosage of
0.5 mmol/L, and a commercial herbicide Fenoxaprop-P-ethyl was used as positive control

NATURAL PRODUCT RESEARCH
5
Table 1. Inꢀibiꢁꢄꢅy ꢅꢆꢁꢊꢂ ꢄf ꢁꢆꢅgꢊꢁ ꢇꢄmpꢄꢉnꢃꢂ ꢆgꢆinꢂꢁ ꢂix pꢆꢁꢀꢄgꢊniꢇ fꢉngi in vitro.
Inhibitory ratio under 0.2 mmol/L (%)
Compd.
R. solani
F. graminearum
A. solani
F. oxysporum
S. sclerotiorum
P. oryzae
a
b
c
d
e
f
g
h
i
48.6 ± 1.2
46.9 ± 0.9
14.9 ± 0.9
39.4 ± 0.6
34.8 ± 1.5
55.4 ± 0.2
59.3 ± 1.9
36.5 ± 0.3
44.6 ± 1.2
13.9 ± 0.8
72.7 ± 2.3
37.1 ± 1.6
49.9 ± 0.3
52.8 ± 0.2
50.7 ± 2.2
13.9 ± 1.0
59.0 ± 0.3
35.5 ± 1.5
33.5 ± 1.2
89.5 ± 1.5
26.3 ± 0.9
28.8 ± 0.6
27.1 ± 0.6
28.8 ± 0.6
24.9 ± 0.3
43.7 ± 0.6
47.0 ± 2.1
29.3 ± 0.3
33.2 ± 1.3
21.0 ± 0.3
27.7 ± 1.3
22.1 ± 2.1
59.7 ± 0.3
21.6 ± 1.5
28.2 ± 0.3
23.8 ± 0.6
28.8 ± 0.6
26.0 ± 2.4
26.0 ± 0.3
92.8 ± 1.5
35.4 ± 0.9
36.7 ± 0.6
33.0 ± 0.0
32.0 ± 0.9
36.0 ± 0.9
56.1 ± 0.3
54.0 ± 0.9
39.8 ± 1.2
39.8 ± 4.2
31.7 ± 0.3
65.1 ± 0.3
41.0 ± 0.9
47.2 ± 0.3
31.7 ± 0.3
40.4 ± 1.5
33.6 ± 1.5
63.8 ± 0.7
36.0 ± 0.9
38.5 ± 1.0
82.1 ± 0.3
12.5 ± 0.3
10.0 ± 0.6
15.0 ± 1.5
11.9 ± 1.5
37.7 ± 0.3
18.2 ± 0.3
17.5 ± 0.0
17.5 ± 0.0
23.8 ± 3.3
12.5 ± 0.3
16.9 ± 0.3
15.7 ± 0.6
35.2 ± 1.2
19.4 ± 0.0
11.9 ± 0.0
14.4 ± 0.3
18.2 ± 0.3
17.5 ± 0.0
19.4 ± 0.0
73.6 ± 0.6
14.2 ± 0.3
28.2 ± 1.2
18.3 ± 0.9
30.8 ± 2.0
23.5 ± 3.2
46.5 ± 4.7
47.5 ± 3.6
16.8 ± 2.2
36.0 ± 4.4
12.6 ± 0.3
36.0 ± 1.7
15.2 ± 1.7
47.5 ± 5.0
51.7 ± 9.3
19.4 ± 1.0
11.6 ± 0.0
35.5 ± 7.8
26.7 ± 3.2
31.9 ± 8.1
87.5 ± 2.1
24.7 ± 0.0
29.3 ± 0.0
24.7 ± 0.6
26.2 ± 0.3
38.6 ± 0.0
82.0 ± 1.2
71.2 ± 0.6
43.3 ± 0.6
27.8 ± 1.5
24.7 ± 0.6
38.6 ± 0.0
51.0 ± 4.8
35.5 ± 3.2
31.6 ± 0.6
27.0 ± 0.0
54.9 ± 0.0
58.0 ± 1.3
41.7 ± 0.3
46.4 ± 0.3
86.0 ± 0.0
j
k
l
m
n
o
p
q
r
s
PCA
Nꢄꢁꢊꢂ: eꢆꢇꢀ ꢁꢅꢊꢆꢁmꢊnꢁ ꢀꢆꢃ ꢁꢀꢅꢊꢊ ꢅꢊpꢈiꢇꢆꢁꢊꢂ (Mꢊꢆn ± sd). tꢀꢊ pꢀꢊnꢆzinꢊ-1ꢇꢆꢅbꢄxyꢈiꢇ ꢆꢇiꢃ (Pca) wꢆꢂ ꢉꢂꢊꢃ ꢆꢂ ꢁꢀꢊ pꢄꢂiꢁivꢊ
ꢇꢄnꢁꢅꢄꢈ.
Table 2. hꢊꢅbiꢇiꢃꢆꢈ ꢆꢇꢁiviꢁy ꢄf ꢁꢆꢅgꢊꢁ ꢇꢄmpꢄꢉnꢃꢂ ꢆgꢆinꢂꢁ barnyard grass ꢆnꢃ rape. (Inꢀibiꢁiꢄn ꢅꢆꢁꢊ/%).
Barnyard grass
Rape
Compd.
Root
Stalk
Root
Stalk
a
0.0 ± 0.0
41.4 ± 4.8
45.3 ± 6.2
73.8 ± 1.7
33.8 ± 5.2
20.1 ± 3.2
8.2 ± 4.3
42.2 ± 4.0
47.7 ± 3.1
2.7 ± 3.3
60.4 ± 6.0
21.0 ± 3.6
33.8 ± 3.3
50.5 ± 4.7
69.2 ± 3.5
56.6 ± 4.7
60.0 ± 5.0
22.6 ± 6.3
22.8 ± 4.4
41.0 ± 4.9
26.2 ± 3.9
70.9 ± 0.9
41.9 ± 7.8
36.9 ± 12.3
89.5 ± 4.1
66.0 ± 9.6
39.7 ± 6.7
53.9 ± 8.8
37.5 ± 10.4
49.5 ± 8.2
42.3 ± 7.9
36.5 ± 9.8
40.7 ± 8.4
51.5 ± 8.5
69.1 ± 8.9
32.7 ± 11.9
100.0 ± 0.0
37.3 ± 13.0
54.1 ± 9.1
38.9 ± 4.9
49.6 ± 7.1
40.3 ± 11.5
62.5 ± 6.2
47.5 ± 3.6
48.3 ± 6.1
68.3 ± 6.1
60.1 ± 6.1
38.7 ± 4.7
53.7 ± 2.4
56.4 ± 7.2
51.2 ± 2.9
59.9 ± 3.7
54.4 ± 5.3
45.8 ± 4.5
51.3 ± 4.6
59.8 ± 8.1
45.4 ± 4.4
100.0 ± 0.0
36.1 ± 7.9
49.4 ± 10.2
44.1 ± 4.2
45.5 ± 5.4
50.5 ± 7.7
36.3 ± 4.6
b
59.4 ± 10.4
95.6 ± 1.7
25.5 ± 4.7
0.0 ± 0.0
c
d
e
f
0.0 ± 0.0
g
19.1 ± 9.1
81.3 ± 4.8
0.0 ± 0.0
h
i
j
43.1 ± 10.8
7.6 ± 11.3
22.5 ± 8.0
49.3 ± 7.6
81.5 ± 3.9
97.7 ± 1.1
74.3 ± 5.4
50.2 ± 4.6
22.5 ± 7.0
88.2 ± 4.3
63.4 ± 6.5
84.7 ± 1.6
k
l
m
n
o
p
q
r
s
PCA
Fꢊnꢄxꢆpꢅꢄp-P-ꢊꢁꢀyꢈ
Nꢄꢁꢊꢂ: eꢆꢇꢀ ꢁꢅꢊꢆꢁmꢊnꢁ ꢀꢆꢃ ꢁꢀꢅꢊꢊ ꢅꢊpꢈiꢇꢆꢁꢊꢂ (Mꢊꢆn ± sd). tꢀꢊ Fꢊnꢄxꢆpꢅꢄp-P-ꢊꢁꢀyꢈ wꢆꢂ ꢉꢂꢊꢃ ꢆꢂ ꢁꢀꢊ pꢄꢂiꢁivꢊ ꢇꢄnꢁꢅꢄꢈ. aꢈꢈ ꢇꢄm-
pꢄꢉnꢃꢂ wꢊꢅꢊ ꢁꢊꢂꢁꢊꢃ ꢆꢁ ꢁꢀꢊ ꢇꢄnꢇꢊnꢁꢅꢆꢁiꢄn ꢄf 0.5 mmꢄꢈ/l.
at the same concentration. Their herbicidal activities are listed inTable 2. The results indicated
that, most target compounds showed herbicidal activities against barnyard grass and rape,
and compounds c, o and s exhibited potent herbicidal activities against barnyard grass root

6
X. ZHU ET AL.
length, with the inhibition rates of 95.6, 97.7, 88.2%, respectively, which were higher than
those of the positive control herbicide Fenoxaprop-P-ethyl (84.7%). Moreover, compound
c also exhibited better herbicidal activities (73.8%) against barnyard grass stalk length than
positive control herbicide Fenoxaprop-P-ethyl (70.9%). Especially, compound o exhibited
1
00% inhibition against the rape in both root length and stalk length, and showed excellent
and wide spectrum herbicidal activities against both gramineae and dicotyledones plants.
Three compounds (e, f, and i) had selective activities against dicotyledones and no toxic
harm to gramineae.
Compounds c, o, and s were chosen as the typical compounds to determine IC values
5
0
against barnyard grass and rape, which exhibited more than 85% inhibitory activity against
barnyard grass and rape stalk length or root length. The IC values of the chosen compounds
50
are presented in Table 3. The most effective compound against barnyard grass root length
was o with an IC = 0.067 mmol, and compound c exhibited the best activity against barn-
50
yard grass stalk length with the IC50 value of 0.158 mmol/L, which is comparable to the
positive control herbicide Fenoxaprop-P-ethyl with its IC values of 0.176 and 0.184 mmol/L
50
against barnyard grass stalk length and root length respectively. Compound o exhibited the
most potent activity against rape both in root length and stalk length with IC50 values of
0
.048 mmol/L and 0.059 mmol/L respectively, 6 to 8 folds lower than the IC values of pos-
50
itive control herbicide Fenoxaprop-P-ethyl.
To analysis the preliminary structure-activity relationships, the herbicidal activities of
compounds a-m with R = aroyl groups were compared to the compounds o-s with
R = alkanoyl groups. It is shown that the structures of R as alkanoyl groups help to improve
their herbicidal activities. Particularly, compounds o with R = 1-naphthalene acetyl exhibited
best herbicidal activities against gramineae and dicotyledones among all of target com-
pounds. We speculate that it may due to the 1-naphthylacetic acid, which is regarded as an
important plant growth regulator. Further comparison of the compounds a-m with R = aroyl
groups, showed that, the compounds of aromatic ring substituted at the same position with
CH , C(CH ) (d, g) generally exhibited better herbicidal activities than the componds sub-
3
3 3
stituted with F, CF (l, i). It implied that introducing electron-donating group substituents in
3
aromatic ring was beneficial to herbicidal activities. Additionally, compound e showed worse
herbicidal activities than b and c, which revealed the substituents of the aroyl groups in the
para-position indicated lower herbicidal activities than other position. And the introduction
of halogen atoms, such as fluorine atom or helium atom, had no obvious effect on herbicidal
activities.
Table 3. Ic vꢆꢈꢉꢊꢂ (mmꢄꢈ/l) ꢄf pꢀꢊnꢆzinꢊ-1-ꢇꢆꢅbꢄxyꢈiꢇ ꢆꢇiꢃ ꢃiꢆmiꢃꢊ ꢃꢊꢅivꢆꢁivꢊꢂ.
5
0
Barnyard grass
Rape
Compd.
Root
Stalk
Root
Stalk
c
o
s
0.073 ± 0.006
0.067 ± 0.003
0.122 ± 0.005
0.176 ± 0.005
0.158 ± 0.004
0.399 ± 0.008
>0.5
0.100 ± 0.007
0.048 ± 0.003
0.463 ± 0.011
0.322 ± 0.006
0.226 ± 0.006
0.059 ± 0.005
>0.5
Fꢊnꢄxꢆpꢅꢄp-P-ꢊꢁꢀyꢈ
0.184 ± 0.004
>0.5
Nꢄꢁꢊꢂ: eꢆꢇꢀ ꢁꢅꢊꢆꢁmꢊnꢁ ꢀꢆꢃ ꢁꢀꢅꢊꢊ ꢅꢊpꢈiꢇꢆꢁꢊꢂ (Mꢊꢆn ± sd). tꢀꢊ Fꢊnꢄxꢆpꢅꢄp-P-ꢊꢁꢀyꢈ wꢆꢂ ꢉꢂꢊꢃ ꢆꢂ ꢁꢀꢊ pꢄꢂiꢁivꢊ ꢇꢄnꢁꢅꢄꢈ.

NATURAL PRODUCT RESEARCH
7
3
. Conclusion
In summary, we have successfully synthesised a series of novel phenazine-1-carboxylic acid
1
diamide derivatives a-s, and their structures were confirmed by H-NMR and HRMS. The
bioassays showed that some of compounds exhibited promising in vitro fungicidal activities
against six phytopathogenic fungi. Surprisingly, most target compounds displayed herbicidal
activities against barnyard grass and rape, and some of them showed potent herbicidal
activities, such as compounds c, o and s. Especially, compound o exhibited the most potent
activity among all the target compounds against rape both in root length and stalk length
with its IC50 values of 0.048 and 0.059 mmol/L respectively. The analysis of preliminary
Structure-Activity Relationships indicated that, the structures of R as alkanoyl groups and
electron-donating group substituents of the aroyl groups were beneficial to herbicidal activ-
ities. The substituents of the aroyl groups in the para-position indicated lower herbicidal
activities than other position. The synthesis, fungicidal activities and herbicidal activities
study of phenazine-1-carboxylic acid diamide derivatives provides the theoretical basis for
further design of phenazine-1-carboxylic acid.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by Natural Science Foundation of China [grant number 31672069]; and
Natural Science Foundation of Hubei Province [grant number 2014CFA105].
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